Interferon induces a protein kinase that is activated by double-stranded RNA in susceptible cells to phosphorylate the alpha subunit of eucaryotic peptide initiation factor 2 (eIF-2). A different protein kinase specific for eIF-2-alpha is activated by heme deficiency in reticulocytes. Both kinases appear to phosphorylate the same site in a 4,000-dalton, terminal segment of eIF-2-alpha with concomitant inhibition of protein synthesis, thereby exerting translation control through a common mechanism. Phosphorylation of both kinases appears to be involved in their activation. Activation of the heme-regulated enzyme involves at least one additional peptide component that is not part of the kinase. Potentially, the state of phosphorylation of eIF-2-alpha can be regulated by either protein kinases or phosphatase activity. Reticulocyte protein phosphatase is a 55,000-dalton peptide which has endogenous M++-dependent protein phosphatase activity. This enzyme has been purified to homogeneity. Its activity is modulated by a number of peptides. Heat-stable activators as well as a series of protease-sensitive peptides have been isolated that affect phosphatase activity. These latter regulatory peptides have been identified by monoclonal antibodies. They are derived by proteolysis from a 230,000-dalton protein that is associated with spectrin in reticulocytes. Work will be directed toward isolation and characterization of components involved in regulation of both the eIF-2-alpha kinase and the protein phosphatase.